Through the development and multidisciplinary analysis of a series of presenilin (PS) mutant mice, we have previously established the physiological functions of the presenilins (PSs) in the central nervous system. During cortical development, presenilins regulate neurogenesis and neuronal migration, primarily through 3- secretase-dependent activation of the Notch signaling pathway. In the adult cerebral cortex, presenilins play a central role in memory, synaptic plasticity and neuronal survival. However, it is unclear if Notch receptors are key mediators of PS functions in the adult cerebral cortex, and whether presenilins carry out these essential functions in a gamma-secretase-dependent or gamma-independent manner. Like PS, Nicastrin (NCT) is an essential component of the gamma-secretase complex, and NCT deficiency in mouse embryonic fibroblasts abolishes gamma- secretase-dependent activities. However, PSs also appear to possess gamma-secretase-independent functions. In this competing renewal application, we propose the following two Specific Aims to address these unanswered questions. First, we will generate and analyze conditional knockout mice lacking Notch1 and/or 2 to determine if inactivation of Notch receptors in the adult cerebral cortex causes memory and synaptic plasticity impairments and neurodegeneration similar to those previously observed in PS conditional double knockout (PS cDKO) mice. Second, we will test if conditional inactivation of NCT in the adult cortex phenocopies PS cDKO mice, and then examine signaling mechanisms previously found to be impaired in PS cDKO mice. The central hypothesis guiding our proposal is that the essential roles of PS in synaptic plasticity, memory and neuronal survival identified in our prior work are mediated via NCT-dependent gamma-secretase activity, possibly through gamma-secretase-dependent activation of Notch signaling. The proposed studies in both Aims will test this central hypothesis and determine if gamma-secretase-independent activity of PS contributes significantly towards its essential functions in the adult brain. The significance of our proposed study is that we will uncover the physiological roles of Notch and NCT in the adult cerebral cortex, which are presently unknown, and determine whether the essential roles of PS in adult brain function depend exclusively on gamma-secretase activity, especially gamma-secretase-dependent activation of Notch signaling. Our long-term goal is to understand the normal functions of presenilins and their downstream effectors in the adult brain. Insight into normal PS function may in turn shed light on the pathogenic mechanisms underlying dementia and neurodegeneration in Alzheimer's disease and frontotemporal dementia. PUBLIC HEALTH RELEVANCE: Mutations in the presenilin genes have been linked to Alzheimer's disease and frontotemporal dementia. In the current application, we propose to investigate how presenilins are involved in memory maintenance and neuronal survival. Better understanding of the molecular pathways by which presenilins regulate cognitive and neuronal integrity will provide important insights into the pathogenesis of these disorders and may provide novel therapeutic targets.